Biological Implications of a Stroke Therapy Based in Neuroglobin Hyaluronate Nanoparticles. Neuroprotective Role and Molecular Bases

Exogenous neuroprotective protein neuroglobin (Ngb) cannot cross the blood–brain barrier. To overcome this difficulty, we synthesized hyaluronate nanoparticles (NPs), able to deliver Ngb into the brain in an animal model of stroke (MCAO). These NPs effectively reached neurons, and were microscopically identified after 24 h of reperfusion. Compared to MCAO non-treated animals, those treated with Ngb-NPs showed survival rates up to 50% higher, and better neurological scores. Tissue damage improved with the treatment, but no changes in the infarct volume or in the oxidative/nitrosative values were detected. A proteomics approach (p-value < 0.02; fold change = 0.05) in the infarcted areas showed a total of 219 proteins that significantly changed their expression after stroke and treatment with Ngb-NPs. Of special interest, are proteins such as FBXO7 and NTRK2, which were downexpressed in stroke, but overexpressed after treatment with Ngb-NPs; and ATX2L, which was overexpressed only under the effect of Ngb. Interestingly, the proteins affected by the treatment with Ngb were involved in mitochondrial function and cell death, endocytosis, protein metabolism, cytoskeletal remodeling, or synaptic function, and in regenerative processes, such as dendritogenesis, neuritogenesis, or sinaptogenesis. Consequently, our pharmaceutical preparation may open new therapeutic scopes for stroke and possibly for other neurodegenerative pathologies.

Designing the Armadillo Orthosis: User experience design for a wearable upper limb stroke therapy device.

<p>Stroke is a medical condition causing disability worldwide (Feigin et al., 2014; Murray et al., 2012; National Heart Lung and Blood institute, 2016). It can leave people with physical and cognitive deficits. The individual’s function in everyday activities following a stroke depends on the severity of the stroke and the amount of therapy available to them. Rehabilitation for the physical impairments, such as upper limb deficits, can promote recovery and is delivered by physiotherapists and occupational therapists. Therapy takes place predominantly in the clinical environment. It is manual, task based, delivered one on one, and can be time intensive. Self-management methods for patients’ stroke rehabilitation are gaining attention from healthcare professionals (Taylor, Monsanto, Kilgour, Smith, & Hale, 2019). Rehabilitation that can be done at home has benefits for the individual, the family or caregiver, the therapist and the healthcare system. Independent rehabilitation at home reduces pressure on healthcare resources and can be beneficial for stroke patients recovery. So, medical interventions and products are shifting from clinical to community and home environments. The use of robotics for rehabilitation has the potential to support recovery of function and assist with everyday tasks in a variety of ways. This paper explores the design of a robotic device for the hand. By involving stroke patients, clinicians and carers in the design process, this research aims to improve the user experiences of a robotic device for hand rehabilitation. Designing for the user experience has the potential to improve the engagement and acceptance of the robotic device for independent home therapy. A combination of methods have been used to include users in the design process and gather qualitative data to inform the design. The methodologies include research through design and human-centred design. Research through design includes methods such as a literature review, using and adapting design criteria, prototyping, iteration, user-testing, and thematic analysis. Human-centred design is about involving users in the development process and include methods such as surveys, semi-structured interviews, observations, and user testing. There were four clinicians and seven stroke patients that met inclusion criteria and participated in the testing. Three patients and three clinician participants were involved in the interviews. Personas were used to understand user wants and needs, and to inform criteria for the design process. By using these methods we gain a better understanding of the users’ needs in order to improve the design of the pre-existing robotic upper limb stroke rehabilitation device. The purpose of the design is to meet the needs of the stroke patient in his or her own home. This design study focuses on developing the user experience by addressing usability. Interactions considered during the iterative design process are putting on and taking off the device. It is found through testing and iterations that comfort, cleaning and safety were necessary for this wearable robotic upper limb stroke therapy device to be easily worn and used in the home.</p>

Designing the Armadillo Orthosis: User experience design for a wearable upper limb stroke therapy device.

<p>Stroke is a medical condition causing disability worldwide (Feigin et al., 2014; Murray et al., 2012; National Heart Lung and Blood institute, 2016). It can leave people with physical and cognitive deficits. The individual’s function in everyday activities following a stroke depends on the severity of the stroke and the amount of therapy available to them. Rehabilitation for the physical impairments, such as upper limb deficits, can promote recovery and is delivered by physiotherapists and occupational therapists. Therapy takes place predominantly in the clinical environment. It is manual, task based, delivered one on one, and can be time intensive. Self-management methods for patients’ stroke rehabilitation are gaining attention from healthcare professionals (Taylor, Monsanto, Kilgour, Smith, & Hale, 2019). Rehabilitation that can be done at home has benefits for the individual, the family or caregiver, the therapist and the healthcare system. Independent rehabilitation at home reduces pressure on healthcare resources and can be beneficial for stroke patients recovery. So, medical interventions and products are shifting from clinical to community and home environments. The use of robotics for rehabilitation has the potential to support recovery of function and assist with everyday tasks in a variety of ways. This paper explores the design of a robotic device for the hand. By involving stroke patients, clinicians and carers in the design process, this research aims to improve the user experiences of a robotic device for hand rehabilitation. Designing for the user experience has the potential to improve the engagement and acceptance of the robotic device for independent home therapy. A combination of methods have been used to include users in the design process and gather qualitative data to inform the design. The methodologies include research through design and human-centred design. Research through design includes methods such as a literature review, using and adapting design criteria, prototyping, iteration, user-testing, and thematic analysis. Human-centred design is about involving users in the development process and include methods such as surveys, semi-structured interviews, observations, and user testing. There were four clinicians and seven stroke patients that met inclusion criteria and participated in the testing. Three patients and three clinician participants were involved in the interviews. Personas were used to understand user wants and needs, and to inform criteria for the design process. By using these methods we gain a better understanding of the users’ needs in order to improve the design of the pre-existing robotic upper limb stroke rehabilitation device. The purpose of the design is to meet the needs of the stroke patient in his or her own home. This design study focuses on developing the user experience by addressing usability. Interactions considered during the iterative design process are putting on and taking off the device. It is found through testing and iterations that comfort, cleaning and safety were necessary for this wearable robotic upper limb stroke therapy device to be easily worn and used in the home.</p>

Abstract 1122‐000237: Prior Vascular Risk Factors Affecting Presentation Time and Utilization of Acute Ischemic Stroke Therapies

Introduction : Multiple factors have been reported to influence the time between onset of symptoms in acute ischemic stroke and hospital presentation. Although education level is one independent factor in presentation, as we previously reported, health literacy has not been fully assessed regarding specific patient knowledge on stroke or its known risk factors. This study aims to determine whether having a history of vascular risk factors such as prior stroke, coronary artery disease (CAD), or atrial fibrillation (AF) influence presentation time and acute ischemic stroke therapy utilization. Methods : This study included 250 acute ischemic stroke patients presenting to a large academic community hospital from February to December 2018. Educational level was defined within four categories: Grade School, High School, College or Higher, and Unknown. Last seen normal, symptom onset, and arrival times were acquired. Vascular risk factors chosen for this study included prior stroke, CAD, and AF. History of vascular risk factors was verified by medical documentation showing prior diagnosis by physician. Initial NIH Stroke Scale score, stroke location, vessel involved, LDL, hemoglobin A1c, gender, and race were also obtained. Patients were categorized based on their level of education, the presence or absence of vascular risk factors, and utilization of tPA or thrombectomy (MT). The primary outcomes were onset‐to‐arrival time (OTA), in minutes, and utilization rates of acute ischemic stroke therapies (either tPA, MT, or both). Subgroup analysis was conducted to associate education level with each vascular risk factor, comparing OTA and acute ischemic stroke therapy utilization rate. Results : As previously reported, educational level was inversely associated with OTA and positively associated with utilization of at least one acute ischemic stroke therapy. Prior stroke, CAD, and AF showed a substantial OTA decrease for all education groups except for College. Prior stroke decreased OTA in Grade School by 24% (764 vs. 579); High School by 30% (222 vs. 154) and College by 20% (52 vs. 41). CAD decreased OTA in Grade School by 65% (734 vs. 253), High School by 14% (209 vs. 180), and College by 3% (50 vs 49). AF decreased OTA in Grade School by 88% (764 vs. 91) and High School by 56% (216 vs. 95), but increased in College by 35% (47 vs. 64). History of prior stroke decreased utilization of both tPA and MT by 14%; CAD increased tPA use by 8% and MT by 5%; while AF increased tPA use by 9% and MT by 12%. Conclusions : Having at least one prior vascular risk factor (prior stroke, CAD, AF), diagnosed by a physician, was associated with lower OTA in Grade School and High School educated patients. A history of prior stroke was associated with lower acute stroke therapy utilization (tpa and MT), while both CAD and AF were associated with increased acute stroke therapy utilization.

Extended Mechanism and Rate-Limiting Step of the Plasminogen Activator Staphylokinase Revealed by Global Kinetic Analysis

The plasminogen activator staphylokinase is a fibrin-specific thrombolytic biomolecule and an attractive target for the development of effective myocardial infarction and stroke therapy. To engineer the protein rationally, a detailed understanding of the biochemical mechanism and limiting steps is essential. Conventional fitting to equations derived based on simplifying approximations may be inaccurate for complex mechanisms like that of staphylokinase. We employed a modern numerical approach of global kinetic data analysis whereby steady-state kinetics and binding affinity datasets were analyzed in parallel. Our approach provided an extended, revised understanding of the staphylokinase mechanism without simplifying approximations and determined the value of turnover number kcat of 117 s-1 that was 10,000-fold higher than that reported in the literature. The model further showed that the rate-limiting step of the catalytic cycle is the binding of staphylokinase to plasmin molecules, which occurs via an induced-fit mechanism. The overall staphylokinase effectivity is further influenced by the formation of an inactive staphylokinase.plasminogen complex. Here, we describe a quick and simplified guide for obtaining reliable estimates of key parameters whose determination is critical to fully understand the staphylokinase catalytic functionality and define rational strategies for its engineering. Our study provides an interesting example of how global numerical analysis of kinetic data can be used to better understand the mechanism and limiting factors of complex biochemical processes.

Mechanical Thrombectomy as the Treatment of Choice for Ischemic Stroke Large Vessel Acocclusion

Despite major advances in stroke management in the last 2 decades, stroke is still the leading cause of disability and death worldwide. Current ischemic stroke therapy aims to improve long-term outcomes in stroke patients. For this purpose, early recanalization is the only promising therapy for acute ischemic stroke. The main goal of reperfusion therapy in acute ischemic stroke is to immediately improve blood flow (recanalization) in areas of the brain that are ischemic and have not undergone infarction. The long-term goal is to increase outcomes by reducing disability and death from stroke. The most important factor in the success of reperfusion therapy in acute ischemic stroke is therapy as early as possible. However, selection of suitable candidates for reperfusion therapy requires neurologic evaluation and neuroimaging studies.

Heparin and Arginine Based Plasmin Nanoformulation for Ischemic Stroke Therapy

Ischemic stroke is the most common type of stroke and thrombolytic therapy is the only approved treatment. However, current thrombolytic therapy with tissue plasminogen activator (tPA) is often hampered by the increased risk of hemorrhage. Plasmin, a direct fibrinolytic, has a significantly superior hemostatic safety profile; however, if injected intravenously it becomes rapidly inactivated by anti-plasmin. Nanoformulations have been shown to increase drug stability and half-life and hence could be applied to increase the plasmin therapeutic efficacy. Here in this paper, we report a novel heparin and arginine-based plasmin nanoformulation that exhibits increased plasmin stability and efficacy. In vitro studies revealed significant plasmin stability in the presence of anti-plasmin and efficient fibrinolytic activity. In addition, these particles showed no significant toxicity or oxidative stress effects in human brain microvascular endothelial cells, and no significant blood brain barrier permeability. Further, in a mouse photothrombotic stroke model, plasmin nanoparticles exhibited significant efficacy in reducing stroke volume without overt intracerebral hemorrhage (ICH) compared to free plasmin treatment. The study shows the potential of a plasmin nanoformulation in ischemic stroke therapy.